Human cancer therapy based on the adoptive transfer of T lymphocytes has relied on T cell populations with poorly defined functional characteristics and consequently, poor clinical results. Recent work in this laboratory has documented that CD4+ Th2 helper T cells account for the majority of infiltrating T cells in human renal cell carcinoma. We have demonstrated that these cells secrete virtually no IL-2 following TcR/CD3 stimulation. In contrast, TcR/CD3 stimulation causes the secretion of IL-4 which has been identified as a potent inhibitor of NK and CTL responses. The functional characteristics of Th2 may in part be responsible for the absence of effective CTL immunity and thus, disease progression. We began our preclinical studies on ovarian cancer by examining the biology of the host immune response to both solid tumor and malignant ascites. Our results indicate that T cells obtained from malignant ascites possess tumor-specific tumoricidal activity against tumor obtained from ascites. Likewise, T cells isolated from solid tumor possess tumor-specific tumoricidal activity against solid tumor. T cells from solid tumor also efficiently kill ascitic tumor. However, we have demonstrated that T cells from ascites do not efficiently kill solid tumor. Thus, metastatic ovarian cancer is not only characterized by two distinct clinical forms of disease but these two forms of disease are also immunologically distinguished by the tumor-bearing host. These results suggest that in the therapeutic setting, use of T cells obtained from ascites will not provide optimum therapeutic benefit to the patient with ovarian cancer since tumor will not effectively trigger ascitic T cell cytotoxic activity. The objective of this application are to establish the biological profile of T cells with therapeutic efficacy as well as those T cells with tumor- promoting characteristics.
The specific aims are (1) To determine the functional characteristics of tumor-specific CD8+ CTL isolated from malignant ascites and solid tumor. (2) To correlate specific CTL functional traits with specific TcR variable (V) genes. (3) To determine the functional characteristics of tumor-specific CD4+ helper T cells isolated from malignant ascites and solid tumor. (4) To correlate specific helper cell functional characteristics with specific TcR variable (V) genes. (5) To identify tumor-derived peptides as targets of CTL immunity.
